The active component of marijuana, Delta(9)-tetrahydrocannabinol, activates the CB1 and CB2 cannabinoid receptors, thus mimicking the action of endogenous cannabinoids. CB1 is predominantly neuronal and mediates the cannabinoid psychotropic effects. CB2 is predominantly expressed in peripheral tissues, mainly in pathological conditions. So far the main endocannabinoids, anandamide and 2-arachidonoylglycerol, have been found in bone at ‘brain’ levels. The CB1 receptor is present mainly in skeletal sympathetic nerve terminals, thus regulating the adrenergic tonic restrain of bone formation. CB2 is expressed in osteoblasts and osteoclasts, stimulates bone formation, and inhibits bone resorption. Because low bone mass is the only spontaneous phenotype so far reported in CB2 mutant mice, it appears that the main physiologic involvement of CB2 is associated with maintaining bone remodeling at balance, thus protecting the skeleton against age-related bone loss. Indeed, in humans, polymorphisms in CNR2, the gene encoding CB2, are strongly associated with postmenopausal osteoporosis. Preclinical studies have shown that a synthetic CB2-specific agonist rescues ovariectomy-induced bone loss. Taken together, the reports on cannabinoid receptors in mice and humans pave the way for the development of 1) diagnostic measures to identify osteoporosis-susceptible polymorphisms in CNR2, and 2) cannabinoid drugs to combat osteoporosis.